Every clinical trial with therapeutic intent is an experiment involving a set of subjects, an intervention, a set of objectives, and methods of achieving those objectives. An important challenge in the context of drug development is to enhance the validity of trial observations by controlling the impact of relevant variables on observations. The definition of inclusion and exclusion criteria is an especially important step because the patient population is one of the most important variables that may affect the outcome of a trial.
The other important consideration is an ethical obligation to respect the rights of subjects and reduce the risks to their health and wellbeing. When designing clinical trials, there is always a need to balance the desire to include a well-selected patient population to reduce heterogeneity with the opportunity to include a broader population that could benefit from the treatment.
In recent decades, there have been issues with the definition of eligibility criteria, particularly in early phase/FIH clinical trials and oncology.
Ethical and Scientific Considerations for Defining Eligibility Criteria
From a CRO perspective, we often see that inclusion criteria tend to be restrictive, and this has several repercussions. From a scientific perspective, when there is hyper-selection of patients, the immediate risk is a lack of external validity, as the data from the trial may not accurately reflect the benefit/risk profile of the drug due to the underrepresented diversity of the cancer patient population.
Early phase clinical trials provide a unique opportunity to find different dose levels to test in different tumor types and in a wider population, so there is a need for broader eligibility criteria. This way, information gathered from a broader population could ultimately optimize the drug development process.
From an ethical perspective, we recognize that groups such as adolescents, pregnant women, and elderly patients are often excluded from clinical trials. But also, the concept of drug development and clinical research itself could be compromised if patients are seen as means to developing the drug rather than benefiting from the opportunity to be treated.
In some cases, we see a repetition of inclusion criteria from one study to another, and the restriction of inclusion criteria may be based on the need to target specific populations with specific biomarkers and/or mutations. However, this decision could also be related to a conservative approach that avoids patients with certain comorbidities that could mask the potential efficacy of the treatment.
Ultimately, discussing the possibilities of designing eligibility criteria, options for patients who cannot access clinical trials, and how to broaden inclusion criteria has become a topic of interest for patient communities, investigators, clinical research organizations, sponsors, and regulatory agencies.
Recent approaches from scientific societies, regulatory organizations and working groups
In 2016, ASCO held a multistakeholder workshop to identify scientific opportunities for expanding clinical trial eligibility criteria. Prior to that, patient advocates, biotech manufacturers, investigators, and regulators performed some analysis of the state of the science and developed recommendations for the following topics:
- Brain metastases
- Organ dysfunction
- Eligibility for enrollment
The ASCO-Friends of Cancer Research Brain Metastases Working Group published the full recommendations, with the main recommendation being to expand eligibility to be more inclusive of patients with treated/stable brain metastases for at least 4 weeks before study entry in prospective clinical trials of all phases. Specifically, for early phase clinical trials, the panel recommended considering including patients with active brain metastases in a separate expansion cohort early in clinical development, particularly if there is a clinical development plan for a drug targeting a population where brain metastases are common.1
The HIV working group reported the final recommendation with regard to evaluation of immune function and criteria related to HIV therapy. The working group concluded that HIV infection alone should not be considered an exclusion criterion in any study. Eligibility criteria related to HIV should take into account an approach to concurrent antiretroviral therapy and criteria related to immune status appropriate for a given study.2
The workshop on organ dysfunction (renal, hepatic, cardiac) prior and concurrent malignancies, hematological malignancies, and comorbidities outlined several areas in which modifying current clinical trial eligibility could enhance trial participation.3
After these recommendations were published, their impact was perceived in the clinical trial design of subsequent studies, although the integration and implementation of some of these recommendations remains difficult, as it requires coordination and collaboration among multiple stakeholders, including principal investigators, pharmaceutical companies, institutions, and patients.
Clinical trial eligibility
Of importance is that the Food and Drug Administration Reauthorization Act (FDARA) of 2017 required FDA to convene a public meeting to discuss clinical trial eligibility criteria to inform a guidance on this subject. This public workshop was held in April 2018, and the results were made public.4 As done previously by ASCO-Friends, the discussion held at the FDA workshop represented an important step in ongoing efforts to move towards more inclusionary clinical research.
Previously, workshops led by ASCO-Friends resulted in the development of a series of guidance documents by the U.S. Food and Drug Administration regarding recommendations for eligibility criteria for clinical trials of drugs or biological products.5–8
Subsequently, the ASCO–Friends of Cancer Research Prior Therapies Work Group published the results of a workshop held in 2021 on clinical cancer research.9 This represented another step forward in the overall process of increasing awareness regarding eligibility criteria by focusing on prior exposure to therapy and advising clinical trial designers and sponsors to clarify and justify any restrictions based on prior therapies.
It is important to note that the above publications and guidance documents released by the FDA are recommendations and are not mandatory requirements. However, this demonstrates that there is a need to increase awareness about this topic and the potential to improve and optimize the design of clinical trials and eligibility criteria, especially in early phase oncology.
Evolving oncology clinical research
Here at Precision for Medicine, we take pride in supporting our clients, whether small biotechs or mid-size pharmaceutical companies, during every step of their clinical development. Specifically, we invest time and energy and pay particular attention to the examination of the protocol or study concept. We provide our clients with a full analysis and scientific considerations, covering the study design, study endpoints, operational strategy, and a detailed granular analysis of the eligibility criteria.
As reported above, we observe frequently that there is a conservative approach and lack of knowledge of recent updates on this subject, and therefore, many clinical trials tend to report a copy of the inclusion/exclusion criteria from previous/oldest CTs. Our role as oncologists and medical experts in the CRO environment is to scrutinize the eligibility criteria, provide the most recent results and discussion from organizations, institutions, and regulatory agencies, but more importantly, share the lessons learned from previous studies: what made them successful and what could represent a potential failure or trigger for early protocol amendment.
The study design and the definition of inclusion and exclusion criteria remain critical and vital steps that require excellent and knowledgeable planning to increase the rate of success in drug development, but also by promoting patient-centered clinical trials.
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- Lin NU, et al. J Clin Oncology. 2017.
- Uldrick TS, et al. J Clin Oncology. 2017.
- Lichtman, et al. J Clin Oncology. 2017.
- U.S. Food and Drug Administration. Evaluating Inclusion and Exclusion Criteria in Clinical Trials. 2018. https://www.fda.gov/media/134754/download
- U.S. Food and Drug Administration. Guidance Document: Cancer Clinical Trial Eligibility Criteria: Brain Metastases 2020; Available from: https://www.fda.gov/media/121317/download
- U.S. Food and Drug Administration. Guidance Document: Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections. 2020; Available from: https://www.fda.gov/media/121319/download
- U.S. Food and Drug Administration. Guidance Document: Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients. 2020; Available from: https://www.fda.gov/media/121318/download
- U.S. Food and Drug Administration. Guidance Document: Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies. 2020; Available from: https://www.fda.gov/media/123745/download
- Osarogiagbon, et al. Clin Cancer Research. 2021.